Antibacterial agents III

ABSTRACT

Novel 1-amino-naphthyridine- and quinoline-carboxylic acids as antibacterial agents are described as well as methods for their manufacture, formulation, and use in treating bacterial infections.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,341,784 discloses certain substituted7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacids having the general formula: ##STR1## The compounds are disclosedto have antibacterial activity. The Journal of Medicinal Chemistry, 23,1358 (1980) discloses certain substituted quinoline-3-carboxylic acidshaving the structural formula ##STR2## may be pyrrolidinyl. See alsoU.S. Pat. No. 4,146,719. The compounds are disclosed to haveantibacterial activity.

European Patent Application No. 81 10 6747, Publication No. 047,005,published Mar. 10, 1982, discloses certain benzoxazine derivativeshaving the structural formula ##STR3## wherein A is halogen and B may bea cyclic amine substituent such as pyrrolidine, or piperidine.

Certain 7-heterocyclic substituted 1,8-naphthyridines are disclosed inEur. J. Med. Chem. Chimica Therapeutica, 29, 27 (1977). U.S. Pat. Nos.3,753,993 and 3,907,808 disclose certain 7-pyridylquinolines.

European patent publication no. 90 424 discloses1-R-1,4-dihydro-4-oxo-6-fluoro-7-(Z=N)-quinolinecarboxylic acids andesters thereof where R is amino, lower alkylamino, 2-propenylamino ordi-lower alkylamino and Z-N is preferably 1-piperazinyl or 4-loweralkyl-1-piperazinyl. The compounds are illustrated by the generalformula ##STR4##

The references teach that these compounds possess antibacterialactivity.

SUMMARY OF THE INVENTION

The invention in a first generic chemical compound aspect is a compoundhaving the structural formula I ##STR5## wherein Z is ##STR6## X is CH,CF or N; Y is hydrogen or amino; n is 1, 2, 3, or 4;

n' is 1, 2, 3, or 4 wherein n+n' is a total of 2, 3, 4, or 5, and

n" is 0, 1, or 2; n'" is 0, 1, or 2;

n^(iv) is 1, 2, or 3;

R₁ is hydrogen, alkyl having from one to six carbon atoms or a cation;

R₃ is hydrogen, alkyl having from one to four carbon atoms or cycloalkylhaving three to six carbon atoms;

R₄ is hydrogen, alkyl from one to four carbon atoms, hydroxyalkyl havingtwo to four carbon atoms, trifluoroethyl or R₇ CO-- wherein R₇ is alkylhaving from one to four carbon atoms, or alkoxy having from one to fourcarbon atoms;

R₅ is hydrogen, or alkyl having from one to three carbon atoms;

R₆ is hydrogen or alkyl having from one to three carbon atoms, and thepharmaceutically acceptable acid addition or base salts thereof.

The preferred compounds of this invention are those wherein Z is##STR7## Also preferred compounds of this invention are those wherein Zis ##STR8##

Other preferred compounds of this invention are those wherein Y ishydrogen. Other preferred compounds of this invention are those whereinX is CH or C--F.

Other preferred compounds of this invention are those wherein R₁ ishydrogen or a pharmaceutically acceptable base salt such as a metal oramine salt.

Other preferred compounds of this invention are those wherein n" is one,R₃ is hydrogen, methyl, ethyl, or n-propyl, and R₄, R₅, and R₆ arehydrogen.

The most preferred compounds are those wherein Y is hydrogen, X is CH orCF, Z is ##STR9## R₁ is hydrogen and R₃ is hydrogen, methyl, ethyl, 1-or 2-propyl, or a pharmaceutically acceptable acid addition or base saltthereof.

Particularly preferred species of the invention are the compounds havingthe names:

7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid;

7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid;

7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-di-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid;

7-[3-(aminomethyl)-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6-fluoro-1-methylamino-7-(7-ethyl-2,7-diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid;

6,8-difluoro-1,4-dihydro-1-methylamino-7-(7-ethyl-2,7diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6-fluoro-1-methylamino-7-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid;

6,8-difluoro-1,4-dihydro-1-methylamino-7-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6-fluoro-1-methylamino-7-(2,7-diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6,8-difluoro-1-methylamino-7-(2,7-diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid;

7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-6-fluoro-1-methylamino-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6-fluoro-1-methylamino-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6-fluoro-1-methylamino-7-[3-[(propylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6,8-difluoro-1-methylamino-7-[3-[(propylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6-fluoro-1-methylamino-7-[3-[(2-propylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6,8-difluoro-1-methylamino-7-[3-[(2propylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid;

7-[3-[(cyclopropylamino)methyl]-1-pyrrolidinyl]-1,4-dihydro-6-fluoro-1-methylamino-4-oxo-3-quinolinecarboxylicacid;

7-[3-[(cyclopropylamino)methyl]-1-pyrrolidinyl]-1,4-dihydro-6,8-difluoro-1-methylamino-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6-fluoro-1-methylamino-4-oxo-7-[3-[[(2,2,2-trifluoroethyl)amino]methyl]-1-pyrrolidinyl]-3-quinolinecarboxylicacid;

1,4-dihydro-6,8-difluoro-1-methylamino-4-oxo-7-[3[[(2,2,2-trifluoroethyl)amino]methyl]-1-pyrrolidinyl]-3-quinolinecarboxylicacid;

1,4-dihydro-6-fluoro-7-[3-[[(2-hydroxyethyl)amino]methyl]-1-pyrrolidinyl]-1-methylamino-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6,8-difluoro-7-[3-[[(2-hydroxyethyl)amino]methyl]-1-pyrrolidinyl]-1-methylamino-4-oxo-3-quinolinecarboxylicacid;

7-[3-(aminomethyl)-1-pyrrolidinyl]-1,4-dihydro-6-fluoro-1-methylamino-4-oxo-3-quinolinecarboxylicacid;

1,4-dihydro-6,8-difluoro-1-methylamino-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid, and the pharmaceutically acceptable acid addition or base saltsthereof.

The following process for preparing compounds of the formula ##STR10##wherein R₁, X, Y, and Z are as defined for formula I which comprisesreacting a compound having the following structural formula ##STR11##with an amine corresponding to the group Z wherein Z is the compoundhaving the structural formula ##STR12## wherein all of the above termsare as defined in formulae I and L is a leaving group which ispreferably fluorine or chlorine.

The invention also includes a pharmaceutical composition which comprisesan antibacterially effective amount of a compound having structuralformula I and the pharmaceutically acceptable salts thereof incombination with a pharmaceutically acceptable carrier. The inventionfurther includes a method for treating bacterial infections in a mammalwhich comprises administering an antibacterially effective amount of theabove defined pharmaceutical composition to a mammal in need thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compounds of the invention having the structural formula I may bereadily prepared by treating a corresponding compound having thestructural formula II with the desired cyclic amine III or IIIa. Forpurposes of this reaction, the alkylamine substituent of Compound III orIIIa may, if desired, be protected by a group which renders itsubstantially inert to the reaction conditions. Thus, for example,protecting groups such as the following may be utilized:

carboxylic acyl groups such as formyl, acetyl, trifluoroacetyl;

alkoxycarbonyl groups such as ethoxycarbonyl,

t-butoxycarbonyl, β,β,β-trichloroethoxycarbonyl, β-iodoethoxycarbonyl;

aryloxycarbonyl groups such as benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, phenoxycarbonyl;

silyl groups such trimethylsilyl; and groups such as trityl,tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl,diphenylphosphinyl, p-toluenesulfonyl, and benzyl, may all be utilized.

The protecting group may be removed, after the reaction between CompoundIV and Compound Va or Vb if desired, by procedures known to thoseskilled in the art. For example, the ethoxycarbonyl group may be removedby acid or base hydrolysis and the trityl group may be removed byhydrogenolysis.

The reaction between the compound of structural formula II and asuitably protected compound of formula III or IIIa may be performed withor without a solvent, preferably at elevated temperature for asufficient time so that the reaction is substantially complete. Thereaction is preferably carried out in the presence of an acid acceptorsuch as an alkali metal or alkaline earth metal carbonate orbicarbonate, a tertiary amine such as triethylamine, pyridine, orpicoline. Alternatively an excess of the compound of formula III or IIIamay be utilized as the acid acceptor.

Convenient solvents for this reaction are nonreactive solvents such asacetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide,dimethylformamide, pyridine, picoline, water, and the like. Solventmixtures may also be utilized.

Convenient reaction temperatures are in the range of from about 20° toabout 150° C.; higher temperatures usually require shorter reactiontimes.

The removal of the protecting group R₄ may be accomplished either beforeor after isolating the product, I. Alternatively, the protecting groupR4 need not be removed.

The starting compounds having structural formulae II are known in theart or, if new, may be prepared from known starting materials bystandard procedures or by variations thereof. Thus the followingcompound is disclosed in the noted reference: ##STR13##

The6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid may also be prepared by a method described in European PatentPublication No. 90 424A. This compound may be converted to thecorresponding5-amino-6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid by first nitrating the above compound with potassium nitrate andsulfuric acid then hydrogenating the nitro group catalytically withpalladium on carbon according to known methods. An alternate method forpreparing the above starting material is described in the Examples.

The compounds of the invention having structural formula III or IIIa areeither known compounds or they may be prepared from known startingmaterials by standard procedures or by variations thereof. For example,3-pyrrolidinemethanamines having the structural formula D ##STR14## maybe readily prepared from the known starting material methyl5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate, A, [J. Org. Chem., 26,1519 (1961)]by the following reaction sequence. ##STR15##

The compound wherein R₃ is hydrogen, namely 3-pyrrolidinemethanamine,has been reported in J. Org. Chem., 26, 4955 (1961).

Thus Compound A may be converted to the corresponding amide B bytreatment with R₃ NH₂ ; for example, a saturated solution of ethylaminein an alkanol such as methyl alcohol may be utilized. The diamide B maynext be reduced to produce the corresponding diamine C. This reductionmay be carried out using lithium aluminum hydride, for example, in aconvenient solvent such as tetrahydrofuran. Compound C may next bedebenzylated, for example using hydrogen and 20% palladium on carboncatalyst to produce the diamine D. Alternatively, when R₃ =H in C, theprimary amine function may be protected with a group R₄ as defined,hereinabove. For example, the primary amine function may be acylatedwith an acyl halide such as acetyl chloride by well known procedures.The primary amine function of C may also be converted to a carbamateester such as the ethyl ester by treatment with ethyl chloroformate inthe presence of a strong base such as 1,8-diazabicyclo[5.4.0]undec-7-enein a convenient solvent such as methylene chloride. The benzyl group maynext be removed, for example as described above for Compound C, therebyproducing Compound D where R is --CO₂ Et, which after conversion to acompound of the type Va or Vb may be reacted with a compound having thestructural formula IV to thereby produce a corresponding compound havingthe structural formulae I. The --CO₂ Et group may be removed by standardprocedures.

Likewise spiroamino compounds represented by structural formula Vb maybe readily prepared from the known starting material3-ethoxycarbonyl-5-oxo-3-pyrrolidineacetic acid ethyl ester [J. Org.Chem., 46, 2757 (1981)]by the following reaction sequence. ##STR16##

The compound 2,7-diazaspiro [4.4]nonane where R₃ is H is described inthe above reference. Thus Compound E may be converted to thecorresponding amide F by treatment with R₃ NH₂, for example, methylamine in water followed by benzylation which may be carried out withsodium hydride and benzyl chloride to give G. Reduction to the diamine Hmay be accomplished with lithium aluminum hydride. Subsequentdebenzylation, for example, with hydrogen and 20% palladium on carboncatalyst produces the diamine J.

The compounds of the invention display antibacterial activity whentested by the microtitration dilution method as described in Heifetz, etal, Antimicr. Agents & Chemoth., 6, 124 (1974), which is incorporatedherein by reference.

By use of the above referenced method, the followed minimum inhibitoryconcentration values (MICs in μg/ml) were obtained for representativecompounds of the invention.

    ______________________________________                                        IN VITRO ANTIBACTERIAL ACTIVITY                                               Minimal Inhibitory Concentration                                              MIC (μg/ml)                                                                                 Com-    Com-    Com-  Com-                                                    pound   pound   pound pound                                  Organisms        Ex. 1   Ex. 2   Ex. 3 Ex. 4                                  ______________________________________                                        Enterobacter cloacae MA 2646                                                                   6.3     0.8     0.2   1.6                                    Escherichia coli Vogel                                                                         12.5    0.2     0.2   1.6                                    Klebsiella pneumoniae MGH-2                                                                    6.3     0.2     0.2   1.6                                    Proteus rettgeri M 1771                                                                        25      0.4     1.6   1.6                                    Pseudomonas aeruginosa UI-18                                                                   25      0.2     0.8   1.6                                    Staphylococcus aureus H 228                                                                    12.5    3.1     0.4   1.6                                    Staphylococcus aureus UC-76                                                                    0.2     0.4     0.2   0.2                                    Streptococcus faecalis MGH-2                                                                   6.3     12.5    0.4   0.8                                    Streptococcus pneumoniae SV-1                                                                  3.1     6.3     0.1   0.8                                    Streptococcus pyogenes C-203                                                                   0.4     0.8     0.2   0.2                                    ______________________________________                                    

The compounds of the invention are capable of forming bothpharmaceutically acceptable acid addition and/or base salts. Base saltsare formed with metals or amines, such as alkali and alkaline earthmetals or organic amines. Examples of metals used as cations are sodium,potassium, magnesium, calcium, and the like. Examples of suitable aminesare N,N'-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

Pharmaceutically acceptable acid addition salts are formed with organicand inorganic acids.

Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and thelike. The salts are prepared by contacting the free base form with asufficient amount of the desired acid to produce either a mono or di,etc salt in the conventional manner. The free base forms may beregenerated by treating the salt form with a base. For example, dilutesolutions of aqueous base may be utilized. Dilute aqueous sodiumhydroxide, potassium carbonate, ammonia, and sodium bicarbonatesolutions are suitable for this purpose. The free base forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but the salts are otherwise equivalentto their respective free base forms for purposes of the invention. Useof excess base where R' is hydrogen gives the corresponding basic salt.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms. In general, the solvatedforms, including hydrated forms and the like are equivalent to theunsolvated forms for purposes of the invention. DBT-1 -17

The alkyl groups contemplated by the invention comprise both straightand branched carbon chains of from one to about three carbon atomsexcept when specifically stated to be greater than three carbon atoms.Representative of such groups are methyl, ethyl, propyl, isopropyl, andthe like.

The cycloalkyl groups contemplated by the invention comprise thosehaving three to six carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

Certain compounds of the invention may exist in optically active forms.The pure D isomer, pure L isomer as well as mixtures thereof; includingthe racemic mixtures, are contemplated by the invention. Additionalassymmetric carbon atoms may be present in a substituent such as analkyl group. All such isomers as well as mixtures thereof are intendedto be included in the invention.

The compounds of the invention can be prepared and administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise asthe active component, either a compound of formula I or a correspondingpharmaceutically acceptable salt of a compound of formula I.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersable granules, capsules, cachets, and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablets disintegrating agents; it can also be anencapsulating material. In powders, the carrier is a finely dividedsolid which is in admixture with the finely divided active compound. thetablet the active compound is mixed with carrier having the necessarybinding properties in suitable proportions and compacted in the shapeand size desired. The powders and tablets preferably contain from 5 or10 to about 70 percent of the active ingredient. Suitable solid carriersare magnesium carbonate, magnesium sterate, talc, sugar, lactose,pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodiumcarboxymethyl cellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets, and capsulescan be used as solid dosage forms suitable for oral administration.

Liquid form preparations include solutions suspensions and emulsions. Asan example may be mentioned water or water-propylene glycol solutionsfor parenteral injection. Such solutions are prepared so as to beacceptable to biological systems (isotonicity, pH, etc). Liquidpreparations can also be formulated in solution in aqueous polyethyleneglycol solution. Aqueous solutions suitable for oral use can be preparedby dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents as desired.Aqueous suspension suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, i.e.,natural or synthetic gums, resins, methyl cellulose, sodiumcarboxymethyl cellulose, and other well-known suspending agents.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantites of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself or it can be the appropriate number of any of thesepackaged forms.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 mg to 100 mg according to the particularapplication and the potency of the active ingredient.

In therapeutic use as agents for treating bacterial infections thecompounds utilized in the pharmaceutical method of this invention areadministered at the initial dosage of about 3 mg to about 40 mg perkilogram daily. A daily dose range of about 6 mg to about 14 mg perkilogram is preferred. The dosages, however, may be varied dependingupon the requirements of the patient, the severity of the conditionbeing treated, and the compound being employed. Determination of theproper dosage for a particular situation is within the skill of the att.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

PREPARATION OF STARTING MATERIALS EXAMPLE AN-methyl-3-pyrrolidinemethanamineN-methyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide

A mixture of 100 g (0.43 mole) of methyl5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519(1961)], 500 ml methanol and 100 g (3.2 mole) of methylamine was heatedat 100° C. in a pressure reactor for 16 hours. The reaction mixture wascooled and the ammonia and methanol were removed under reduced pressure.The residue was taken up in dichloromethane and washed with 3×100 ml 1Nsodium hydroxide. The organic layer was dried over magnesium sulfate andthe solvent removed at reduced pressure to give 88.3 g ofN-methyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as a whitesolid, mp 82.5°-83.0° C.

This material was used in the next step.

N-methyl-1-(phenylmethyl)-3-pyrrolidinemethanamine

To a suspension of 37.40 g (1.00 mole) lithium aluminum hydride in 1000ml tetrahydrofuran, was added a solution of 88.3 g (0.380 mole) ofN-methyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide in tetrafurandropwise under nitrogen. The reaction was then refluxed overnight. Thereaction flask was cooled in an ice bath and 37.4 ml of water, 37.4 mlof 15% sodium hydroxide and 112.2 ml of water were added. Theprecipitated solids were filtered and washed with hot ethanol. Thecombined filtrates were concentrated, then dissolved in dichloromethane,filtered, dried over magnesium sulfate, and the solvent evaporated underreduced pressure to give 68.68 g ofN-methyl-1-(phenylmethyl)-3-pyrrolidinemethanamine as an oil. Thismaterial was used without further purification in the next step.

N-Methyl-3-pyrrolidinemethanamine

A mixture of 67.28 g (0.32 mole) ofN-methyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 3 g of 20% palladiumon carbon, and 600 ml of methanol was shaken in an atmosphere ofhydrogen at about 50 psi and at room temperature for 18 hours. Another 3g of 20% palladium on carbon was added and the hydrogenation continuedfor 6.5 hours. Another 3.0 g of 20% palladium on charcoal was added andthe hydrogenation continued for another 4.5 hours. The catalyst wasfiltered and the filtrate evaporated under reduced pressure. The residuewas distilled under vacuum (72°-76° C., 10.5 mm Hg) to give 8.32 gN-methyl-3-pyrrolidinemethanamine.

EXAMPLE B N-Ethyl-3-pyrrolidinemethanamineN-Ethyl-5-oxo-1-(phenylmethyl)-3-pyrrolidine-carboxamide

A mixture of 200 g (0.86 mole) of methyl5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519(1961)], 1000 ml methanol and 200 g (4.4 mole) of ethylamine was heatedat 100° C. in a pressure reactor for 17.2 hours. The reaction mixturewas cooled and the excess ethylamine and methanol were removed underreduced pressure. The residue was taken up in dichloromethane and washedwith 3×150 ml 1N sodium hydroxide. The organic layer was dried overmagnesium sulfate and the solvent removed at reduced pressure to give104.6 g of N-ethyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as awhite solid, mp 97°-99° C.

This material was used in the next step.

N-Ethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine

To a suspension of 108.68 g (2.860 mole) lithium aluminum hydride in 800ml tetrahydrofuran, was added a solution of 194.5 g (0.790 mole) ofN-ethyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide in 600 mltetrahydrofuran dropwise under nitrogen. The reaction was then refluxedfour hours. The reaction flask was cooled in an ice bath and 108 ml ofwater, 108 ml of 15% sodium hydroxide, and 324 ml of water were added.The precipitated solids were filtered and washed with hot ethanol. Thecombined filtrates were concentrated, then dissolved in dichloromethane,filtered, dried over magnesium sulfate, and the solvent evaporated underreduced pressure to give 151.9 g ofN-ethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine as an oil.

This material was used without further purification in the next step.

N-Ethyl-3-pyrrolidinemethanamine

A mixture of 151.65 g (0.695 mole) ofN-ethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 5 g of 20% palladiumon carbon, and 1100 ml of ethanol was shaken in an atmosphere ofhydrogen at about 50 psi and at room temperature for 21.6 hours. Another5 g of 20% palladium on carbon was added and the hydrogenation continuedfor 24 hours. The catalyst was filtered and the filtrate evaporatedunder reduced pressure. The residue was distilled under vacuum (88°-91°C., 11.5 mm Hg) to give 66.0 g N-ethyl-3-pyrrolidinemethanamine.

EXAMPLE C N-(2,2,2-Trifluoroethyl)-3-pyrrolidinemethanamine5-Oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide

A mixture of 21.9 g (0.100 mole)5-oxo-1-(phenylmethyl)-3-pyrrodlidinecarboxylic acid in 150 mltetrahydrofuran, was cooled to 0° C. in an ice bath under nitrogen and24.32 g (0.150 mole) carbonyl diimidazole was added. The reaction wasstirred at 0° C. for 30 minutes, then at room temperature for 30minutes. A solution of 13.55 g (0.100 mole) of 2,2,2-triflouroethylaminehydrochloride, 15.22 g (0.100 mole) 1,8-diazabicyclo[5.4.0]undec-7-eneand 100 ml tetrahydrofuran was added. The reaction was stirred at roomtemperature overnight. The solvent was removed at reduced pressure. Theresidue was taken up in dichloromethane and washed 3×150 ml saturatedsodium bicarbonate. The organic layer was dried over magnesium sulfateand the solvent removed under reduced pressure. The product was purifiedby column chromatography on silica with ethyl acetate to give 8.50 g of5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide,mp 110°-112° C.

This material was used in the next step.

1-(Phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine

A mixture of 8.50 g (28.3 mole) of5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3pyrrolidinecarboxamidein 100 ml tetrahydrofuran was added dropwise to 3.22 g (84.9 mmole) oflithium aluminum hydride in 50 ml tetrahydrofuran. The reaction wasrefluxed two hours, then stirred at room temperature overnight. Thereaction was cooled in an ice bath and 3.2 ml of water, 3.2 ml of 15%sodium hydroxide, and 9.6 ml of water were added. The precipitated saltswere filtered and washed with hot ethanol. The combined filtrates wereconcentrated under reduced pressure. The residue was taken up indichloromethane, filtered, and dried over magnesium sulfate. The solventwas removed at reduced pressure to give 7.15 g of1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine.

This material was used without further purification in the next step.

N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine

A mixture of 7.15 g (26.3 mmole)1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine 100ml of methanol and 0.7 g of 20% palladium on carbon was shaken in anatmosphere of hydrogen at about 50 psi and at room temperature for 24hours. The catalyst was filtered and the filtrate evaporated underreduced pressure. The residue was distilled under vacuum (63°-65° C.,2.8 mm Hg) to give 2.55 g ofN-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine.

EXAMPLE D N-Propyl-3-pyrrolidinemethanamine5-Oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide

To a solution of 10.96 g (50 mmole) of5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml ofacetonitrile was added 9.73 g (60 mmole) of carbonyldiimidazole. Thereaction was heated to 60° C. for one hour, cooled to room temperatureand treated with 4.13 g (70 mmole) of n-propylamine. After stirring fortwo hours, the solvent was removed in vacuo and the residue partitionedbetween ether and water. The organic layer was washed with water, 1Nhydrochloric acid, dried over magnesium sulfate, filtered, andevaporated invacuo to give 12.0 g of5-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide, mp 86°-87° C.

1-(Phenylmethyl)-N-propyl-3-pyrrolidinemethanamine

To a suspension of 8.2 g (0.2 mole) of lithium aluminum hydride in 150ml of dry tetrahydrofuran was added portionwise, 12.0 g (45.6 mmole) ofsolid 5-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide. When theaddition was complete, the reaction mixture was stirred at roomtemperature for 18 hours and then at reflux for two hours. After coolingto room temperature, the mixture was treated dropwise, successively,with 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml ofwater, titrating the final addition to produce a granular precipitate.The solid was removed by filtration, washed with tetrahydrofuran and thefiltrate evaporated in vacuo to give 9.6 g of1-(phenylmethyl)-N-propyl-3-pyrrolidine methanamine, as a heavy syrup.

This material was used for the next step without further purification.

N-Propyl-3-pyrrolidinemethanamine

A mixture of 14.0 g (60.0 mmole) of1-(phenylmethyl)-N-propyl-3-pyrrolidinemethanamine, 1.0 g of 20%palladium on carbon and 140 ml of methanol was shaken in an atmosphereof hydrogen at about 50 psi and room temperature for 24 hours. Thecatalyst was removed by filtering through Celite, the filtrateconcentrated and distilled in vacuo to give 7.1 g ofN-propyl-3-pyrrolidinemethanamine, bp 49°-50° C./0.25 mm.

EXAMPLE E N-Cyclopropyl-3-pyrrolidinemethanamine5-Oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide

To a solution of 16.4 g (75 mmole) of5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml ofacetonitrile was added 13.8 g (85 mmole) of carbonyldiimidazole. Thereaction was heated to 60° C. for one hour, cooled to room temperatureand treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction wasstirred at room temperature for 18 hours, the solvent removed in vacuoand the residue partitioned between chloroform and water. The organiclayer was washed with water, 1N hydrochloric acid, dried over magnesiumsulfate, filtered, and evaporated in vacuo to give 18.3 g of5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp94°-96° C. 1-(Phenylmethyl)-N-cyclopropyl-3-pyrrolidine-methanamine

To a suspension of 8.2 g (0.20 mole) of lithium aluminum hydride in 150ml of dry tetrahydrofuran was added portionwise 18.0 g (70.0 mmole) ofsolid 5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide.When the addition was complete, the reaction mixture was stirred at roomtemperature for 18 hours and then at reflux for two hours. After coolingto room temperature, the mixture was treated dropwise, successively,with 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml ofwater, titrating the final addition to produce a granular precipitate.The solid was removed by filtration, washed with tetrahydrofuran and thefiltrate evaporated in vacuo to give 16.0 g of1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinemethanamine as a heavy oil.This was used for the next step without further purification.

N-Cyclopropyl-3-pyrrolidinemethanamine

A mixture of 13.6 g (59.0 mmol) of1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinemethanamine, 0.5 g of 20%palladium on carbon and 140 ml of methanol was shaken in an atmosphereof hydrogen at about 50 psi and room temperature for 24 hours. Thecatalyst was removed by filtering through Celite, the filtrateconcentrated and distilled in vacuo to give 6.3 g ofN-cyclopropyl-3-pyrrolidinemethanamine, bp 88°-90° /13 mm.

EXAMPLE F N-(2-Propyl)-3-pyrrolidinemethanamine5-Oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide

To a solution of 16.4 g (75.0 mmole) of5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml ofacetonitrile was added 13.8 g (85.0 mmole) of 1,1'-carbonyldiimidazole.The reaction was heated to 60° C. for one hour, cooled to roomtemperature and treated with 5.0 g (85 mmole) of isopropylamine. Thereaction was stirred at room temperature for 18 hours, the solventremoved in vacuo and the residue partitioned between chloroform andwater. The organic layer was washed with water, 1N hydrochloric acid,dried over magnesium sulfate and evaporated in vacuo to give 18.6 g of5-oxo-1-(phenylmethyl)-N-(2-propyl)3-pyrrolidinecarboxamide, mp122°-124° C.

1-(Phenylmethyl)-N-(2-propyl)-3-pyrrolidinemethanamine

To a suspension of 8.2 g (0.2 mole) of lithium aluminum hydride in 150ml of dry tetrahydrofuran was added portionwise, 18.3 g (70.0 mmole) ofsolid 5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide. Whenthe addition was complete, the reaction mixture was stirred at roomtemperature for 18 hours and then refluxed for two hours. After coolingto room temperature, the mixture was treated dropwise, successively,with 8 ml of water, 8 ml of 15% aqueous sodium hydroxide and 24 ml ofwater, titrating the final addition to produce a granular precipitate.The solid was removed by filtration, washed with tetrahydrofuran and thefiltrate evaporated in vacuo to give 15.6 g of1-(phenyl-methyl)-N-(2-propyl)-3-pyrrolidinemethanamine as a heavysyrup.

This material was used for the next step without further purification.

N-(2-Propyl)-3-pyrrolidinemethanamine

A mixture of 13.4 g (58.0 mmol) of1-phenylmethyl-N-(2-propyl)-3-pyrrolidinemethanamine, 1.0 g of 20%palladium on carbon and 130 ml of methanol was shaken in an atmosphereof hydrogen at about 50 psi and room temperature for 24 hours. Thecatalyst was removed by filtration through Celite; the filtrateconcentrated and distilled in vacuo to give 6.3 g ofN-(2-propyl)-3-pyrrolidinemethanamine, bp 58°-60° C./3.5 mm.

EXAMPLE G 2-[(3-pyrrolidinylmethyl)amino]ethanolN-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide

A mixture of 46.7 g (1200 mole) of methyl5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate (J. Org. Chem., 26, 1519(1961)], 36.7 g (1600 mole) 2-aminoethanol and 500 ml methanol wererefluxed overnight. The reaction was cooled to room temperature and thesolvent removed at reduced pressure. The residue was taken up indichloromethane and extracted 3×100 1N sodium hydroxide. The aqueouslayer was taken to pH 5, extracted with 3×150 ml dichloromethane, thentaken to pH 8 and again extracted with 3×150 ml dichloromethane. Theaqueous layer was concentrated at reduced pressure and the resultingslurry stirred in dichloromethane. The salts were filtered off. Thecombined organic layers were dried over magnesium sulfate, the solventremoved at reduced pressure to yield 47.9 g ofN-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as anoil. This was used in the next step without further purification.

2-[[[1-(phenylmethyl)-3-pyrrolidinyl]methyl]amino] ethanol.

A mixture of 46.66 g (0.178 mole) ofN-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide in200 ml of tetrahydrofuran was added dropwise to a slurry of 20.25 g(0.534 mole) of lithium aluminum hydride in 150 ml tetrahydrofuran. Thereaction was refluxed three hours, then cooled in an ice bath. The workup consisted of sequential addition of 20 ml water, 20 ml 15% sodiumhydroxide then 60 ml water. The reaction was filtered and theprecipitate washed with ethanol. The filtrate was concentrated atreduced pressure, the residue taken up in dichloromethane, dried overmagnesium sulfate, and the solvent removed at reduced pressure to give32.31 g of 2-[[[1-(phenylmethyl)-3-pyrrolidinyl]methyl]amino]ethanol asan oil. This material was used in the next step without furtherpurification.

2-[(3-pyrrolidinylmethyl)amino]ethanol

A mixture of 32.32 g of2-[[[1-(phenylmethyl)3-pyrrolidinyl]methyl]amino]ethanol, 330 ml ofmethanol and 3 g of 20% palladium on charcoal was shaken in anatmosphere of hydrogen at about 50 psi and at room temperature for 18hours. The solvents were then removed at reduced pressure. The residuewas distilled under vacuum (bp 129°-131° C. 1.5 mm Hg) to give 11.43 gof 2-[(3-pyrrolidinyl methyl)amino] ethanol.

EXAMPLE H 2-Methyl-2,7-diazaspiro[4.4]nonane Dihydrochloride2-Methyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione

A solution of 20.3 g (0.084 mole)3-ethoxycarbonyl-5-oxo-3-pyrrolidineacetic acid, ethyl ester [J. Org.Chem. 46, 2757 (1981)]in 40 ml of 40% aqueous methylamine was stirred atroom temperature overnight, then placed in an oil bath and graduallyheated to 220° C. over 30 minutes allowing volatiles to distill from theopen flask. The crude product was crystallized from ethanol to afford12.56 g of 2-methyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione, mp 201°-204°C.

2-Methyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]-nonane-1,3,8-trione

A solution of 1.82 g (10 mmol)2-methyl-2,7diazaspiro[4.4]nonane-1,3,8-trione in 20 mlN,N-dimethylformamide was added gradually under a nitrogen atmosphere to0.050 g (10.4 mmol) of 50% oil suspension of sodium hydride which hadbeen previously washed twice with toluene and covered with 10 mlN,N-dimethylformamide. After stirring one hour there was added 1.40 g(11 mmol) of benzyl chloride and stirring was continued overnight atroom temperature. After concentrating to a small volume in vacuo, theresidue was diluted with 40 ml water and extracted twice withdichloromethane. The combined organic phase was washed with water, driedover magnesium sulfate, and evaporated to give a solid. Crystallizationfrom toluene-hexane afforded 1.74 g of2-methyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonane-1,3,8-trione, mp157°-158° C. 2-Methyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonaneDihydrochloride

A solution of 1.36 g (5.0 mmol)2-methyl-7-(phenylmethy)-2,7-diazaspiro[4.4]nonane-1,3,8-trione in 50 mltetrahydrofuran was added dropwise to a suspension of 0.95 g (25 mmol)lithium aluminum hydride in 30 ml tetrahydrofuran. Ihe mixture wasstirred overnight at room temperature, refluxed one hour, cooled, andtreated dropwise with 0.95 ml water, 0.95 ml 15% sodium hydroxidesolution and 2.8 ml water. After removal of the inorganic solids byfiltration, the filtrate was concentrated in vacuo to give a syrup whichwas dissolved in isopropanol and treated with excess 6N hydrogenchloride in isopropanol. Crystallization afforded 0.97 g of2-methyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonane dihydrochloride, mp233-234° C.

2-Methyl-2,7-diazaspiro[4.4]nonane Dihydrochloride

A solution of 2-methyl-7-(phenylmethyl)-2,7-diazaspiro-[4.4]nonanedihydrochloride in 150 ml of methanol with 1.0 g 20% palladium on carboncatalyst was hydrogenated at 50 psi for two days. After filtration, thefiltrate was concentrated to a thick syrup which crystallized onaddition of acetonitrile to give 11.50 g of2-Methyl-2,7diazaspiro[4.4]nonane dihydrochloride, softened at 164° C.and melted at 168°-170° C. EXAMPLE I

2-Ethyl-2,7-diazaspiro[4.4]nonane Dihydrochloride2-Ethyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione

A suspension of 24.33 g (0.100 mmole)3-ethoxycarbonyl-5-oxo-3-pyrrolidineacetic acid, ethyl ester in anexcess of 2N sodium hydroxide, was stirred three hours at roomtemperature, acidified with dilute hydrochloric acid, and evaporated todryness in vacuo. The product, 3-carboxy-5-oxo-3-pyrrolidineacetic acid,was taken up in isopropyl alcohol, separated from insoluble sodiumchloride by filtration, concentrated to a syrup and dissolved in 100 ml70% ethylamine. The solution was gradually heated in an oil bath up to230° C. allowing volates to distill and then maintained at 230°-240° C.for ten minutes. After cooling, the product was crystallized fromisopropyl alcohol to afford 10.12 g of2-ethyl2,7-diazaspiro[4.4]nonane-1,3,8-trione, mp 168°-169° C.

2-Ethyl-7-(phenylmethyl)-2-7-diazaspiro-[4.4]- nonane-1,3,8-trione

A suspension of sodium hydride (2.20 g of 60% oil suspension (0.055mole) washed with toluene) in 50 ml N,N-dimethylformamide was treatedgradually with a solution of 10.0 g (0.051 mole)2-ethyl-2,7diazaspiro[4.4]nonane-1,3,8-trione in 100 mlN,N-dimethylformamide. After stirring 15 minutes, there was addeddropwise 6.4 ml (0.055 mole) benzyl chloride and the mixture was stirredovernight, concentrated in vacuo and shaken with water-methylenechloride. The organic layer was dried, evaporated, and the productcrystallized from toluene-hexane to afford 11.11 g of2-ethyl-7-(phenylmethyl)-2-7-diazaspiro[4.4]nonane-1,3,8-trione, mp125°-126.5° C.

2-Ethyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonane Dihydrochloride

A solution of 11.00 g (0.0385 mole)2-ethyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonane-1,3,8-trione in 100ml tetrahydrofuran was added dropwise to a suspension of 6.00 g (0.158mole) lithium aluminium hydride in 250 ml tetrahydrofuran. Afterstirring overnight, the mixture was refluxed one hour, cooled, andtreated dropwise with 6 ml water, 6 ml 15% sodium hydroxide, and 18 mlwater. Inorganic solids were separated by filtration and the filtratewas concentrated, taken up in ether, dried with magnesium sulfate, andreevaporated. The resulting syrup was dissolved in isopropyl alcohol andtreated with excess hydrogen chloride in isopropyl alcohol to afford9.63 g of 2-ethyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonanedihydrochloride, mp 196°-198° C. (dec).

2-Ethyl-2,7-diazaspiro[4.4]nonane Dihydrochloride A solution of 9.50 g(0.030 mole) 2-ethyl-7-(phenylmethyl)-2,7-diazaspiro[4.4]nonanedihydrochloride in 100 ml methanol was hydrogenated with 1.0 g 20%palladium on carbon catalyst at 50 psi for 22 hours. After filtration,the solution was concentrated to a syrup and crystallized fromacetonitrile to afford 6.66 g of 2-ethyl-2,7-diazaspiro[4.4]nonanedihydrochloride, mp 168°-172° C. EXAMPLE J 1,1-Dimethylethyl(3-Pyrrolidinyl)carbamate 1,1-Dimethylethyl[1-(Phenylmethyl)-3-pyrrolidinyl]carbamate

A solution of 77.0 g (0.44 mole) of 3-amino-1-(phenylmethyl)pyrrolidine[J. Med. Chem., 24, 1229 (1981)], 440 ml (0.44 mole) 1.0N sodiumhydroxide and 600 ml of tertiary butyl alcohol was treated dropwise with98.2 g (0.45 mole) of di-tertiarybutyl dicarbomate. The reaction wasstirred at room temperature for 18 hours and the solvent removed invacuo. The residue was partitioned between ether and water. The aqueouslayer was reextracted with ether, the combined ether layers were washedwith water, dried (MgSO₄), filtered and evaporated on a steam bathreplacing the ether with petroleum ether. The crystals which formed wereremoved by filtration, washed with ether/petroleum ether (1:1), anddried in vacuo to give 84.8 g of 1,1-dimethylethyl[1-(phenylmethyl)-3-pyrrolidinyl]carbamate, mp 114°-115°. A second crop(16.7 g) was obtained by concentrating the filtrate.

1,1-Dimethylethyl (3-Pyrrolidinyl)carbamate

A mixture of 101.5 g (0.37 mole) of1,1-dimethylethyl[1-(phenylmethyl)-3-pyrrolidinyl]carbamate, 5.0 g of20% Palladium on carbon and 1 liter of tetrahydrofuran was shaken in anatmosphere of hydrogen at about 50 psi and room temperature for 24hours. The catalyst was removed by filtering through Celite, and thefiltrate was concentrated in vacuo to give 6.8 g of 1,1-dimethylethyl(3-pyrrolidinyl)carbamate which solidified upon standing and was ofsufficient purity to be used as is for the ensuing steps.

EXAMPLE K Preparation of1-Methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicAcid 2,3,4,5-Tetrafluorobenzoylacetic acid, Ethyl Ester

To 25.2 g (0.117 mol) of sodium 2,3,4,5-tetrafluorobenzoate, prepared asa dry powder from 2,3,4,5tetrafluorobenzoic acid [J. Org. Chem. 29, 2381(1961)] and aqueous sodium hydroxide with concentration to dryness, wasadded 400 ml of dry ether and the suspension was cooled to 0° C. Slowly25 ml (˜2.5 equivalents) of oxalyl chloride in 50 ml of ether was addedand the mixture brought to room temperature where it was maintained for2.0 hours. It was filtered and concentrated to remove low boilingimpurities. The residue was dissolved in 100 ml of ether and placed inan addition funnel.

Meanwhile, 2.9 g (0.119 mol) of magnesium turnings were treated with 100ml of absolute ethanol and 0.3 ml of carbon tetrachloride. To thismixture was added 18.6 ml (0.12 mol) of diethyl malonate in 75 ml ofether at a rate to keep the temperature just below reflux. When additionwas complete, the reaction was refluxed for two hours. At -20° C., theetheral acid chloride was slowly added. When addition was complete, thereaction was brought to 0° C. over 18 hours. The mixture was poured intodilute hydrochloric acid and was extracted into dichloromethane whichwas dried over magnesium sulfate and concentrated. The residue was thentreated with 340 mg of p-toluenesulfonic acid in 600 ml of water at 100°C. for two hours with rapid stirring. The oil was extracted intodichloromethane, dried over magnesium sulfate and concentrated. Theresidue was purified by column chromatography (Silica gel, usingtoluene:hexane:ether, 4:5:1), to give 18.5 g of a reddish oil. Thismaterial was triturated with pentane to give 10.2 g of2,3,4,5-tetrafluorobenzoylacetic acid, ethyl ester, mp 49°-51° C.

2-[2-(Ethoxycarbonyl)-3-oxo-3-(1,2,3,4-tetrafluorophenyl)-1-propenyl]-1-methylhydrazinecarboxylate,1,1-Dimethylethyl Ester

To 3.0 g (11.33 mmol) of 2,3,4,5-tetrafluorobenzoylacetic acid, ethylester was added 2.49 g of triethylorthoformate and 2.76 g of aceticanhydride. The mixture was heated to 150° C. for 2.5 hours and was thencooled to 80° C. The volitile materials were removed at 0.4 mm Hg forone hour. The residue was then cooled to 45° C. and diluted with 25 mlof isopropyl alcohol. To this solution was added 1.65 g of1-methylhydrazinecarboxylate, 1,1-dimethylethyl ester (Acta ChemicaScandinavica 22, 1, 1968) in 25 ml of isopropyl alcohol. The mixture wasstirred overnight, diluted with 30 ml of pentane and filtered to give3.09 g of2-[2-(ethoxycarbonyl)-3-oxo-3-(1,2,3,4-tetrafluorophenyl)-1-propenyl]-1-methylhydrazinecarboxylate,1,1-dimethylethyl ester as a white solid, mp 130°-131° C.

1-[[(1,1-Dimethylethoxy)carbonyl]methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, Ethyl Ester

To 3.09 g (7.35 mmol) of 2-[2-(ethoxycarbonyl)-3-oxo-3-(1,2,3,4-tetrafluorophenyl)-1-propenyl-1-methylhydrazinecarboxylate,1,1-dimethyethyl ester in 100 ml of dry dioxane was added 0.36 g (1.02equivalent) of sodium hydride (50% dispersion) which was pentane washedprior to addition. The mixture was then refluxed overnight and was leftstanding at room temperature for 24 hours. The mixture was concentratedto a thick oil, taken up in dichloromethane, filtered and extracted withwater twice. The dichloromethane was dried (MgSO₄) and concentrated to aviscous oil which crystallized upon addition of pentane to give 2.39 gof1-[[(1,1-dimethylethoxy)-carbonyl]methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, ethyl ester, mp 99.5°-102° C.

6,7,8-Trifluoro-1,4-dihydro-1-methylamino-4-oxo-3quinolinecarboxylicacid

To 2.00 g (5.0 mmol) of1-[[(1,1-dimethylethoxy)carbonyl]methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, ethyl ester was added 35 ml of acetic acid and 15 ml of 2Nhydrochloric acid. The mixture was placed on a steam bath for 2.5 hours,was diluted with 15 ml of water, and was cooled. The solids werefiltered to give 1.09 g of6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3quinolinecarboxylicacid, mp 237°-238° C.

EXAMPLE 17-[3-[(Ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinolinecarboxylicAcid

A mixture of 0.81 g (3 mmol)7-chloro-6-fluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (European Patent No. 0,090,424) and 1.54 g (12 mmol)-[(ethylamino)methyl]-pyrrolidine in 5 ml pyridine was refluxed 19hours, concentrated to a syrup in vacuo, and diluted with ether toafford a yellow solid. The crude product was dissolved in water,titrated to pH 1.5 with dilute hydrochloric acid, and crystallized frommethanol to afford 0.64 g7-[3-[(ethylamino)methyl]pyrrolidine]-6-fluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, mp 280° C. with decomposition.

EXAMPLE 27-(3-Amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicAcid

To 1.00 g (3.68 mmol) of6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid in 10 ml of acetonitrile was added 0.56 g (1.0 equivalent) of1,8-diazobicyclo-[5,4,0]undec-7-ene and 0.68 g of 1,1-dimethylethyl3-pyrrolidinylcarbamate. The mixture was refluxed for one hour andstirred at room temperature overnight. The solids were filtered andwashed with ether to give 0.92 g of7-[3-[[(1,1dimethylethoxy)carbonyl]amino]-1-pyrro-lidinyl]-6,8-difluoro-1,4-dihydro-1-(methylamino)-4-oxo-3quinolinecarboxylicacid. A portion of this material (0.38 g) was treated with 10 ml oftrifluoroacetic acid for 2 hours and was concentrated. The residue wastaken up in aqueous sodium hydroxide to pH 12.5 and then treated withhydrochloric acid to pH 7.0. The solids were filtered to give 0.24 g of7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid, mp 210°-211° C.

EXAMPLE 37-[3-[(Ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid

To 0.75 g (2.75 mmol) of the6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid in 15 ml of acetonitrile was added 0.44 g (1.05 equivalent) of1,8-diazobicyclo[5.4.0]undec-7-ene, and 0.352 g (1.0 equivalent) ofN-ethyl-3-pyrrolidinemethanamine. The mixture was refluxed for one hourand then stirred at room temperature overnight. The solids were filteredto give 0.68 g of7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid, mp 222°-224° C.

EXAMPLE 47-[3-(Aminomethyl)-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid

To 0.75 g (2.75 mmol) of the6,7,8-trifluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid in 15 ml of acetonitrile was added 0.44 g (1.05 equivalents) of1,8-diazobicyclo[5.4.0]undec-7-ene and 0.275 g (1.0 equivalents) of3-pyrrolidinemethanamine [J. Org. Chem., 26, 4955 (1961)]. The mixturewas refluxed for one hour and stirred at room temperature overnight. Thesolids were filtered to give 0.72 g of7-[3-(aminomethyl)-1-pyrrolidinyl[-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid, mp 150°-180° C. slow dec.

EXAMPLE 5

1,4-Dihydro-6-fluoro-1-methylamino-7-(7-ethyl-2,7-diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 1 by using2-ethyl-2,7-diazaspiro[4.4]nonane as the reacting amine.

EXAMPLE 6

6,8-Difluoro-1,4-dihydro-1-methylamino-7-(7-ethyl-2,7-diazasprio[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 3 by using2-ethyl-2,7-diazaspiro[4.4]nonane as the reacting amine.

EXAMPLE 7

1,4-Dihydro-6-fluoro-1-methylamino-7-(7-methyl-2,7diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 1 by using2-methyl-2,7-diazaspiro[4.4]nonane as the reacting amine.

EXAMPLE 8

6,8-Difluoro-1,4-dihydro-1-methylamino-7-(7ethyl-2,7-diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylic acidmay be prepared by the method in Example 3 by using2-ethyl-2,7-diazaspiro[4.4]nonane as the reacting amine.

EXAMPLE 9

1,4-Dihydro-6-fluoro-1-methylamino-7-(2,7-diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 1 by using 2,7diazaspiro[4.4]nonane [J. Org. Chem. 46, 2757 (1981)] as the reactingamine.

EXAMPLE 10

1,4-Dihydro-6,8-difluoro-1-methylamino-7-(2,7-diazaspiro[4.4]nonan-2-yl)-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 3 by using2,7-diazaspiro[4.4]nonan [J. Org. Chem. 46, 2757 (1981)]as the reactingamine.

EXAMPLE 11

7-(3-Amino-1-pyrrolidinyl)-1,4-dihydro-6-fluoro-1-methylamino-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 2 by using1,1-dimethylethyl 3-pyrrolidinylcarbamate as the reacting amine.

EXAMPLE 12

1,4-Diydro-6-fluoro-1-methylamino-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 3 by usingN-methyl-3-pyrrolidinemethanamine as the reacting amine.

EXAMPLE 13

1,4-Dihydro-6,8-difluoro-1-methylamino-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 3 by usingN-methyl-3-pyrrolidinemethanamine as the reacting amine.

EXAMPLE 14

1,4-Dihydro-6-fluoro-1-methylamino-7-[3-[(propylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 1 by usingN-propyl-3-pyrrolidinemethanamine as the reacting amine.

EXAMPLE 15

1,4-Dihydro-6,8-difluoro-1-methylamino-7-[3-[(propylamino)methyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 3 by usingN-propyl-3-pyrrolidinemethanamine as the reacting amine.

EXAMPLE 16

1,4-Dihydro-6-fluoro-1-methylamino-7-[3-[(2-propylamino)methyl]-1-pyrrolidinyl]-4-oxo-3quinolinecarboxylicacid may be prepared by the method in Example 1 by usingN-(2-propyl)-3pyrrolidinemethanamine as the reacting amine.

EXAMPLE 17

1,4-Dihydro-6,8-difluoro-1-methylamino-7-[3-[(2propylamino)methyl]-1-pyrrolidinyl]-4-oxo-3quinolinecarboxylicacid may be prepared by the method in Example 3 by usingN-(2-propyl)-3-pyrrolidinemethanamine as the reacting amine.

EXAMPLE 18

7-[3-[(Cyclopropylamino)methyl]-1-pyrrolidinyl]-1,4-dihydro-6-fluoro-1-methylamino-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 1 by usingN-cyclopropyl-3pyrrolidinemethanamine as the reacting amine.

EXAMPLE 19

7-[3-[(Cyclopropylamino)methyl]-1-pyrrolidinyl]-1,4-dihydro-6,8-difluoro-1-methylamino-4-oxo-3quinolinecarboxylicacid may be prepared by the method in Example 3 by usingN-cyclopropyl-3pyrrolidinemethanamine as the reacting amine.

EXAMPLE 20

1,4-Dihydro-6-fluoro-1-methylamino-4-oxo-7-[3-[[(2,2,2-trifluoroethyl)amino]methyl]-1-pyrrolidinyl]-3-quinolinecarboxylicacid may be prepared by the method in Example 1 by usingN-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine as the reacting amine.

EXAMPLE 21

1,4-Dihydro-6,8-difluoro-1-methylamino-4-oxo-7-[3-[[(2,2,2-trifluoroethyl)amino]methyl]-1pyrrolidinyl]-3-quinolinecarboxylicacid may be prepared by the method in Example 3 by usingN-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine as the reacting amine.

EXAMPLE 22

1,4-Dihydro-6-fluoro-7-[3-[[(2-hydroxyethyl)amino]methyl]-1-pyrrolidinyl]-1-methylamino-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 1 by using2-[(3-pyrrolidinylmethyl)amino]ethanol as the reacting amine.

EXAMPLE 23

1,4-Dihydro-6,8-difluoro-7-[3-[[(2-hydroxyethyl)amino]methyl]-1-pyrrolidinyl]-1-methylamino-4-oxo-3-quinolinecarboxylicacid can by prepared by the method in Example 3 by using2-[(3-pyrrolidinylmethyl)amino]ethanol as the reacting amine.

EXAMPLE 24

7-[3-(Aminomethyl)-1-pyrrolidinyl]-1,4-dihydro-6-fluoro-1-methylamino-4-oxo-3-quinolinecarboxylicacid may be prepared by the method in Example 1 by using3-pyrrolidinemethanamine as the reacting amine.

We claim:
 1. A compound of the formula ##STR17## wherein Z is ##STR18##wherein R₁ is hydrogen or an alkyl having from one to six carbon atomsor a cation; X is CF or CH, Y is hydrogen or amino; R₃ is hydrogen,alkyl having from one to four carbon atoms or cycloalkyl having three tosix carbon atoms; R₅ is hydrogen or alkyl having from one to threecarbon atoms; R₆ is hydrogen or an alkyl having from one to three carbonatoms; n is one, two, three, or four, n' is one, two, three, or fourwherein n+n' is a total of two, three, four, or five, n'" is zero, oneor two, n^(iv) is one, two, or threee and the pharmaceuticallyaccpetable acid addition or base salts thereof.
 2. A compound of theformula ##STR19## wherein Y is hydrogen:Z is ##STR20## in which n" isone and R₃ is hydrogen, methyl, ethyl, 1- or 2-propyl; X is C--F and R₁is hydrogen or a pharmaceutically acceptable base salt thereof.
 3. Acompound of the formula ##STR21## wherein Z is ##STR22## X is C--F orCH; R₃ is hydrogen, methyl, or ethyl; R₁ is hydrogen, alkyl having fromone to six carbon atoms or a cation, and the pharmaceutically acceptableacid addition or base salts thereof.
 4. The compound7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid.
 5. The compound7-[3-(aminomethyl)-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid.
 6. A pharmaceutical composition comprising an antibacteriallyeffective amount of a compound as claimed in claim 1 or 2 together witha pharmaceutically acceptable carrier.
 7. The method of treatingbacterial infections in mammals which comprises administering to saidmammal a pharmaceutical composition as claimed in claim 6.